ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype

Alessandra Soriani, Alessandra Zingoni, Cristina Cerboni, Maria Luisa Lannitto, Maria Rosaria Ricciardi, Valentina Di Gialleonardo, Marco Cippitelli, Cinzia Fionda, Maria Teresa Petrucci, Anna Guarini, Robin Foà, Angela Santoni

Research output: Contribution to journalArticle

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Abstract

There is much evidence to support a role for natural killer (NK) cells in controlling the progression of multiple myeloma (MM), a malignancy characterized by an abnormal plasma cell proliferation in the bone marrow (BM). Induction of DNA dam - age response has been recently shown capable of enhancing NKG2D ligand (NKG2DL) expression, but nothing is known about DNAM-1 ligand (DNAM-1L) regulation. In this study, we show that myeloma cells treated with low doses of therapeutic agents commonly used in the management of patients with MM, such as doxorubicin, melphalan, and bor - tezomib, up-regulate DNAM-1 and NKG2D ligands. Accordingly, therapeutic drug treatment of MM cells increases NK-cell degranulation, the NKG2D and DNAM-1 receptors being the major triggering molecules. Similar data were also obtained using ex vivo primary plasma cells derived from MM patients. Drug-induced DNAM-1 and NKG2D ligand expression was abolished after treatment with the ATM (ataxia telangiectasia mutated) and ATR (ATM - and RAD3-related) pharmacologic inhibitors caffeine and KU-55933, and was preferentially associated with senescent cells arrested in the G2 phase of the cell cycle. Altogether, our findings have identified a common pathway that can trigger the up-regulation of different NK cell-activating ligands and suggest that NK cells represent an immunosurveillance mechanism toward cells undergoing stress-induced senescent programs.

Original languageEnglish
Pages (from-to)3503-3511
Number of pages9
JournalBlood
Volume113
Issue number15
DOIs
Publication statusPublished - Apr 9 2009

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Ataxia Telangiectasia
Automatic teller machines
Multiple Myeloma
Natural Killer Cells
Up-Regulation
Ligands
Phenotype
Plasma Cells
Plasmas
Drug therapy
Therapeutics
Immunologic Monitoring
Cell Degranulation
Melphalan
G2 Phase
Cell proliferation
Caffeine
Pharmaceutical Preparations
Doxorubicin
Dams

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. / Soriani, Alessandra; Zingoni, Alessandra; Cerboni, Cristina; Lannitto, Maria Luisa; Ricciardi, Maria Rosaria; Gialleonardo, Valentina Di; Cippitelli, Marco; Fionda, Cinzia; Petrucci, Maria Teresa; Guarini, Anna; Foà, Robin; Santoni, Angela.

In: Blood, Vol. 113, No. 15, 09.04.2009, p. 3503-3511.

Research output: Contribution to journalArticle

Soriani, A, Zingoni, A, Cerboni, C, Lannitto, ML, Ricciardi, MR, Gialleonardo, VD, Cippitelli, M, Fionda, C, Petrucci, MT, Guarini, A, Foà, R & Santoni, A 2009, 'ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype', Blood, vol. 113, no. 15, pp. 3503-3511. https://doi.org/10.1182/blood-2008-08-173914
Soriani, Alessandra ; Zingoni, Alessandra ; Cerboni, Cristina ; Lannitto, Maria Luisa ; Ricciardi, Maria Rosaria ; Gialleonardo, Valentina Di ; Cippitelli, Marco ; Fionda, Cinzia ; Petrucci, Maria Teresa ; Guarini, Anna ; Foà, Robin ; Santoni, Angela. / ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. In: Blood. 2009 ; Vol. 113, No. 15. pp. 3503-3511.
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abstract = "There is much evidence to support a role for natural killer (NK) cells in controlling the progression of multiple myeloma (MM), a malignancy characterized by an abnormal plasma cell proliferation in the bone marrow (BM). Induction of DNA dam - age response has been recently shown capable of enhancing NKG2D ligand (NKG2DL) expression, but nothing is known about DNAM-1 ligand (DNAM-1L) regulation. In this study, we show that myeloma cells treated with low doses of therapeutic agents commonly used in the management of patients with MM, such as doxorubicin, melphalan, and bor - tezomib, up-regulate DNAM-1 and NKG2D ligands. Accordingly, therapeutic drug treatment of MM cells increases NK-cell degranulation, the NKG2D and DNAM-1 receptors being the major triggering molecules. Similar data were also obtained using ex vivo primary plasma cells derived from MM patients. Drug-induced DNAM-1 and NKG2D ligand expression was abolished after treatment with the ATM (ataxia telangiectasia mutated) and ATR (ATM - and RAD3-related) pharmacologic inhibitors caffeine and KU-55933, and was preferentially associated with senescent cells arrested in the G2 phase of the cell cycle. Altogether, our findings have identified a common pathway that can trigger the up-regulation of different NK cell-activating ligands and suggest that NK cells represent an immunosurveillance mechanism toward cells undergoing stress-induced senescent programs.",
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AU - Cerboni, Cristina

AU - Lannitto, Maria Luisa

AU - Ricciardi, Maria Rosaria

AU - Gialleonardo, Valentina Di

AU - Cippitelli, Marco

AU - Fionda, Cinzia

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AU - Guarini, Anna

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